tbuckley/cabot-search huggingface dataset:
Molecular characterization correlates of different metastasis in advanced colorectal cancer.
Authors: Yanfeng Xi, Yi Fang, Siqi Chen, Guanghua Lu, Wanglong Deng, Ran Ding, Fanfeng Bu
Journal: Journal of Clinical Oncology (2022)

e15565 Background: As we all know that patients with advanced colorectal cancer (CRC) are often diagnosed with liver-only metastases (LM), pulmonary-only metastases (PM) and widespread metastasis (WM). Various methods have also been applied to molecular mutation detection in CRC, However, the differences in molecular mutation profiles between the different metastatic lesions are unclear. Methods: In the period of September 2019 to January 2022, 376 LM, 111 PM and 116 WM were included in this retrospective analysis. The average age of patients with LM, PM and WM were respectively 61, 63 and 63 (range, 21-86, 39-95, 29-83). The proportion of male patients accounted for about 60% of LM (246/376), PM (69/111) and WM (74/116) . In this study, we retrospectively analyzed the single nucleotide variants (SNV), copy number variation (CNV) and fusion variants, detected in patients with different metastatic lesions by using next-generation sequencing (NGS). Pearson’s chi-square test was used to test differences in mutation frequency. P-values &lt; 0.05 were considered significant. SPSS 26.0 was used for the statistical analyses. Results: In LM, PM and WM analyzed cohorts, SNV was detected in 370, 108 and 114 patients. CNV was detected in 225, 58 and 60 patients, and fusions were detected in 25,7 and 9 patients. In LM, PM and WM analyzed cohorts, the genes with the highest mutation frequency were APC (11.60%, 8.73%, 6.40%), TP53 (8.90%, 7.70%, 5.29%), KRAS (5.90%, 6.67%, 5.03%) . In addition, the SMAD4 mutation frequency was 2.13%, 0.82% and 1.04%, respectively. APC and SMAD4 mutation frequency was higher in LM than PM ( P= 0.012, P= 0.007) and WM ( P &lt; 0.0001, P= 0.008). 1026, 221 and 281 CNV were detected in LM, PM and WM, respectively. The genes with the highest mutation frequency were MYC (43%, 7.24%, 4.63%), MET (5.95%, 7.69%, 5.34%), EGFR (5.36%, 7.24%, 4.63%) and FLT3 (4.39%, 4.98%, 6.05%) in LM, PM and WM. The SMAD4 mutation frequency were 0.58% and 1.07% in LM and WM, which was not detected in PM. No significant difference was found in those CNVs. No characteristic fusions were found in the total analyzed cohorts. Conclusions: The SNV and CNV molecular mutation profiles were similar in LM, PM and WM. However, the genes with higher mutation probability show higher mutation frequency in LM. Compared with PM, SNV of SMAD4 displays a higher mutation frequency in LM. It has been previously reported that LM may display poorer overall survival (OS) compared with PM. Considering the effect of SMAD4 on the prognosis of CRC, this study may provide a possible analysis of the poor prognosis of LM patients. However, there is still a need for more clinical research to support these results.
Educational webcast series targeted to the interprofessional bladder cancer care team improves clinician knowledge, confidence, and competence.
Authors: Susan H. Gitzinger, Bryan Carson Taylor, Vanessa Carranza, Joan B. Fowler, Tina Trieu, Ashley Lilly
Journal: Journal of Clinical Oncology (2022)

e23002 Background: There are an estimated &gt;81,000 new cases of metastatic urothelial bladder cancer (mUBC) diagnosed in the U.S each year, resulting in more than 17,000 deaths. mUBC has been shown to be susceptible to immune checkpoint inhibitors (ICIs), and beyond currently approved first and second line indications, these agents are being studied in bladder-sparing regimens and for high risk NMIBC patients who are BCG-unresponsive. Needs assessments demonstrate educational gaps involved in medication selection, dosing, and immune-related adverse event management as barriers to immunotherapy use by the interprofessional bladder cancer care team. The webcast series, “Key Issues for the Advanced Bladder Cancer Care Clinic: Incorporating Immunotherapy into your Community-Based Urology Practice” was designed specifically for the interprofessional team of bladder cancer clinicians to address unmet educational needs by focusing on the communities where the significant majority of patients are diagnosed, evaluated, and managed. Methods: Four online activities were designed to target urology and uro-oncology community physicians, physician assistants, nurse practitioners, nurses, and pharmacists focused on ICI therapies for bladder cancer, with a focus on the role of the team. Learning and confidence change were objectively assessed by analyzing pre- and post-test results before and after the educational activities. Statistical testing between pre- and post-tests were conducted via chi square analysis with a priori significance set at 0.05. Results: Evaluations were collected from N=706 participants. Knowledge advancements, as determined by significant ( P&lt;0.05) increases in correct responses, were observed in several specific topic areas: recognition of ongoing clinical trials (29% pre-test vs. 69% post-test) biomarkers and treatment selection (43% pre-test vs. 81% post-test) logistical concerns for patients initiating ICIs (60% pre-test vs. 80% post-test) Participant self-reported mean confidence scores increased with statistical significance in implementation of appropriate immunotherapy and in recognizing and mitigating irAEs from pre- to post-test ( P&lt;0.05). Conclusions: As the treatment paradigm for bladder cancer continuously evolves, all members of the oncology healthcare team must be equipped to evolve with it to ensure optimal patient care. This analysis shows that online accredited education can significantly improve the knowledge and confidence of the interprofessional bladder cancer care team in multiple areas surrounding the effective and appropriate use of ICIs.
Age as a factor in the molecular landscape and the tumor-microenvironmental signature of osteosarcoma.
Authors: Andreas Seeber, Andrew Elliott, Jaime Modiano, Gerold Untergasser, Margaret von Mehren, Andrew Rosenberg, Moh'd Khushman, Don S. Dizon, Richard F. Riedel, Jonathan C. Trent, Kai Zimmer, Galina Lagos, Bradley DeNardo, Aaron Sarver, Alberto Puccini, Phillip Walker, Matthew James Oberley, Wolfgang Michael Korn, Domink Wolf, Florian Kocher
Journal: Journal of Clinical Oncology (2022)

11525 Background: Osteosarcoma (OS) incidence is characterized by a bimodal age distribution, with peaks in early adolescence and in adults &gt; 65 years of age. In contrast to adolescents, OS in adults is frequently considered as a secondary neoplasm (i.e., transformation of Paget´s disease of the bone, radiation induced). Yet, the literature is scarce regarding the impact of age on the molecular landscape of OS. Herein, we sought to explore the association between age and the genomic profile as well as the tumor immune microenvironment (TME) in a large cohort of OS patients. Methods: 208 specimens were centrally analysed at the Caris Life Sciences laboratory with DNA seq (NextSeq, 592 gene panel or NovaSeq, whole-exome sequencing), RNA seq (Archer fusion panel or whole-transcriptome sequencing) and immunohistochemistry (IHC). RNA deconvolution and differential expression analyses were performed using the Microenvironment Cell Populations counter method for quantification of immune cell populations and gene expression profiling. The cohort was stratified into three distinct age groups (&lt; 25 years [n = 83], 25-45 years [n = 58], &gt; 45 years [67]). Results: Overall, the most frequently detected mutations were in TP53 (37%), RB1 (13%), ATRX (9%), TERT (6%), PTEN (5%), PIK3CA (4%) and KMT2D (3%). Copy number alterations were most frequently detected in CDK4 (12%), LRIG3 (11%), FLCN (11%), MDM2 (9%), CCND3 (9%), VEGFA (8%), TFEB (8%). Interestingly, age-based stratification revealed an increased frequency of FLCN (19.7 vs 4.7%, p &lt; 0.01), CCND3 (13.9 vs 3.1%, p &lt; 0.05), and HSP90AB1 (11.3 vs 0.0%, p &lt; 0.01), alterations in patients &lt; 25 years compared to &gt; 45 years. TME analysis revealed that patients &gt; 45 years have decreased B-cell abundance compared to patients &lt; 25 years (2.9-fold decrease, p &lt; 0.05) and 25-45 years (4.8-fold decrease, p &lt; 0.05). Although not statistically significant, median transcriptional expression of PD-L1 was numerically increased in patients &gt; 45 years (1.8-fold compared to 25-45 years, p = 0.17; 2.0-fold compared to &lt; 25 years, p = 0.27), which was consistent with increasing rates of IHC PD-L1 expression with age (5.3%, 9.4%, and 17.5%, respectively, p = 0.06). Conclusions: To the best of our knowledge, this study represents the largest cohort of molecularly characterized OS. Age-associated differences in the genetic landscape and TME composition, including increased gene amplifications observed in younger patients and decreased B-cell abundance in older patients, might suggest fundamental underlying molecular and biological differences.
Improved survival from early combined radiotherapy: A phase II clinical study and underlying mechanisms of delaying EGFR-TKI acquired resistance in patients with advanced lung cancer.
Authors: Li Zhang, Ping Peng, Juejun Gong, Yujie Zhang, Qian Chu, Shu Xia, Rui Meng, Yongshun Chen, Guang Han, Peng Zhang, Lu Zhang, Yuan Chen
Journal: Journal of Clinical Oncology (2022)

9114 Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have a significant therapeutic effect in the treatment of advanced non-small-cell lung cancer (NSCLC). However, patients treated with EGFR-TKIs had a median progression-free survival (PFS) of only 8 to 18 months. The occurrence of acquired resistance greatly limits the survival benefit of TKI for NSCLC patients. Extensive efforts have been paid to find a well-tolerated drug or treatment that works before acquired resistance to EGFR-TKI with low toxicity. Focusing on clinical trials of targeted combination radiotherapy, we observed some encouraging results. Methods: Stage IV NSCLC patients with EGFR sensitive mutation (19DEL or 21L858R) have received first-line EGFR TKIs treatment and achieved stable disease or partial response have been enrolled in this prospective, multicenter, randomized controlled, phaseⅡstudy. Recruited from 4 hospitals in China, patients were divided into two groups: Stereotactic Body Radiation Therapy (SBRT) combined with TKIs group as the experimental and TKIs treatment group as an active comparator. The primary endpoint is PFS, and the secondary endpoint aims to overall survival (OS) and safety. To further confirmed these clinical observations in patients, xenograft experiments in nude mice were conducted. To examine the specific mechanism, transcriptome sequencing analysis was performed. Results: Between Mar 2015 and Mar 2018, A total of 61 patients who met the inclusion criteria were randomized to the TKI group and SBRT combined group. The median PFS of the TKI group and SBRT combined group were 9.0 vs 17.6 months (p = 0.016). Meanwhile, the median OS were 23.2 vs 33.6 months (p = 0.026). The total number of patients with T790m was 30(49.1%), and the incidence of T790M did not differ between the two groups. Toxicity data and subgroup analyses including different radiation sites will be presented at the conference. As for the xenograft experiments, data on tumor regression and time of drug resistance of early radiotherapy group was clearly superior to others. Transcriptome sequencing analysis found expression of c-Fos was the key point that led to the phenomena. Conclusions: The addition of SBRT significantly delayed the onset of EGFR TKIs acquired resistance and prolonged the PFS and OS of patients. Radiotherapy for the primary site alone might be superior to metastatic sites. Treatment-related adverse events were generally safe and controllable. The oncogenic role of c-Fos in the effect of radiotherapy on gefitinib resistance and promoting the proliferation of NSCLC cells is confirmed. Clinical trial information: NCT03595644.
Clinical and biomarker results of neoadjuvant phase II study of pembrolizumab and carboplatin plus docetaxel in triple-negative breast cancer (TNBC) (NeoPACT).
Authors: Priyanka Sharma, Shane Richard Stecklein, Rachel Yoder, Joshua M. Staley, Kelsey Schwensen, Anne O'Dea, Lauren Elizabeth Nye, Manana Elia, Deepti Satelli, Gregory Crane, Rashna Madan, Maura F. O'Neil, Jamie L. Wagner, Kelsey E. Larson, Christa Balanoff, Milind A. Phadnis, Andrew K. Godwin, Roberto Salgado, Qamar J. Khan, Joyce O'Shaughnessy
Journal: Journal of Clinical Oncology (2022)

513 Background: Addition of pembrolizumab to anthracycline-taxane-platinum chemotherapy improves pathologic complete response (pCR) and event free survival (EFS) in TNBC. Aim of this study was to assess the efficacy of the anthracycline free neoadjuvant regimen of pembrolizumab plus carboplatin plus docetaxel (Cb+D) in TNBC. Methods: In this multicenter study, eligible patients with stage I-III TNBC received carboplatin (AUC 6) + docetaxel (75 mg/m 2 ) + pembrolizumab (200 mg) every 21 days x 6 cycles. The primary endpoint was pCR (no evidence of invasive tumor in breast and axilla). Secondary endpoints were residual cancer burden (RCB), EFS, toxicity, and immune response biomarkers. RNA isolated from pretreatment tumor tissue was subjected to next generation sequencing. Samples were classified as DNA Damage Immune Response (DDIR) signature and DetermaIO signature positive/negative using predefined cutoffs. Evaluation of stromal tumor infiltrating lymphocytes (sTILs) was performed using standard criteria. Results: 117 patients were enrolled from September 2018 to January 2022. 18% were African American, 39% had node positive disease, 88% had stage II/III disease and 15% had ER/PR 1-10%. Pathologic response information is available for 105 patients. pCR and RCB 0+1 rates were 60% (95% CI 51%-70%) and 71% (95% CI 62%-80%), respectively. Treatment related adverse events led to discontinuation of any trial drug in 12% of patients. Immune adverse events were observed in 28% of patients (Grade ≥3=6%). 47% of patients had sTILs ≥30%, 48% were DetermaIO positive, and 61% DDIR positive. The table describes the impact of these biomarkers on pCR and RCB. The areas under the prediction curve (AUC) for pCR were 0.660, 0.709, and 0.719 for DDIR, sTILs, and DetermaIO respectively. At a median follow up of 21 months, 2-year EFS is 88% in all patients; 98% in pCR group and 82% in no pCR group. Conclusions: Neoadjuvant pembrolizumab plus Cb+D regimen yields pCR of 60% and 2-year EFS of 88% in the absence of adjuvant pembrolizumab. The regimen was well tolerated, and no new toxicity signals were noted. Immune enrichment identified by sTILs or DetermaIO signature was associated with high pCR rates approaching or exceeding 80%. PD-L1 and additional biomarker analyses are ongoing. Clinical trial information: NCT03639948. [Table: see text]
QOL-02. Paediatric medical traumatic stress in children with cancer and their parents: Differences in levels of posttraumatic stress symptoms
Authors: Sandra Klašnja, Ivana Kreft Hausmeister, Marko Kavčič, Robert Masten
Journal: Neuro-Oncology (2022)

Abstract Paediatric medical traumatic stress (PMTS) is a set of children’s and their parents’ psychological and physiological responses to pain, injury, serious illnesses, and other experiences with the medical environment. Paediatric cancer patients have the highest prevalence of PMTS as the illness involves a set of stressors that trigger many negative psychological reactions. Posttraumatic stress symptoms (PTSS) are one of the most common psychopathologies among cancer patients. We examined the incidence of PMTS in children with cancer and their parents due to coping with a serious illness and treatment complications. We analysed the following risk factors for PTSS: selected groups of individuals, medical interventions, complications, and treatment modalities. The study involved 183 parents of 133 children and 63 children and adolescents who were treated between 2009 and 2019 at Clinical Department of Paediatric Haematology and Oncology of Paediatric Clinic in Ljubljana. We collected the data using The Intensity of treatment rating scale 2.0 [IRT-2], PTSD checklist for Children/Parent [PCL-C/PR], The PTSD Checklist for DSM-5 [PCL-5] and The Child PTSD Symptoms Scale for DSM-5 [CPSS-5]. PMTS is frequently present in both, children and their parents, regardless of the cancer type, treatment duration, treatment outcome, and child’s age. Mothers, patients with relapse, patients who were diagnosed after age 5, patients with more intensive treatment, and parents of the latter are at higher risk for PMTS occurrence. Additionally, we found a decreasing trend of traumatic responses after five or more years post cancer diagnosis and that parents are more traumatized than children. Our findings will contribute to the systematic prevention of PMTS and medical trauma and to endeavour to use trauma-informed care.
Combined exome and transcriptome sequencing of non-muscle-invasive bladder cancer: associations between genomic changes, expression subtypes, and clinical outcomes
Authors: Anshita Goel, Douglas G. Ward, Boris Noyvert, Minghao Yu, Naheema S. Gordon, Ben Abbotts, John K. Colbourne, Stephen Kissane, Nicholas D. James, Maurice P. Zeegers, Kar Keung Cheng, Jean-Baptiste Cazier, Celina M. Whalley, Andrew D. Beggs, Claire Palles, Roland Arnold, Richard T. Bryan
Journal: Genome Medicine (2022)

Abstract Background Three-quarters of bladder cancer patients present with early-stage disease (non-muscle-invasive bladder cancer, NMIBC, UICC TNM stages Ta, T1 and Tis); however, most next-generation sequencing studies to date have concentrated on later-stage disease (muscle-invasive BC, stages T2+). We used exome and transcriptome sequencing to comprehensively characterise NMIBCs of all grades and stages to identify prognostic genes and pathways that could facilitate treatment decisions. Tumour grading is based upon microscopy and cellular appearances (grade 1 BCs are less aggressive, and grade 3 BCs are most aggressive), and we chose to also focus on the most clinically complex NMIBC subgroup, those patients with grade 3 pathological stage T1 (G3 pT1) disease. Methods Whole-exome and RNA sequencing were performed in total on 96 primary NMIBCs including 22 G1 pTa, 14 G3 pTa and 53 G3 pT1s, with both exome and RNA sequencing data generated from 75 of these individual samples. Associations between genomic alterations, expression profiles and progression-free survival (PFS) were investigated. Results NMIBCs clustered into 3 expression subtypes with different somatic alteration characteristics. Amplifications of ARNT and ERBB2 were significant indicators of worse PFS across all NMIBCs. High APOBEC mutagenesis and high tumour mutation burden were both potential indicators of better PFS in G3pT1 NMIBCs. The expression of individual genes was not prognostic in BCG-treated G3pT1 NMIBCs; however, downregulated interferon-alpha and gamma response pathways were significantly associated with worse PFS (adjusted p -value &lt; 0.005). Conclusions Multi-omic data may facilitate better prognostication and selection of therapeutic interventions in patients with G3pT1 NMIBC. These findings demonstrate the potential for improving the management of high-risk NMIBC patients and warrant further prospective validation.
SWK-06. Structured transition from pediatric neuro-oncology to adult survivorship follow-up care - Can we close the gap?
Authors: Kerstin Krottendorfer, Alicia-Christina Baumgartner, Alexandra Boehm, Sabina Ziomek, Andreas Peyrl, Hannah Gsell, Carina Schneider, Verena Rosenmayr, Johannes Salomon Gojo, Amedeo Azizi, Sarah Rinner, Sabine Burger, Marlene Huemer, Anna Pucher, Ulrike Leiss
Journal: Neuro-Oncology (2022)

Abstract PURPOSE: Advances in treatment have increased survival rates and quality of life of pediatric CNS tumor patients leading to a growing number of long-term survivors. However, there is sufficient clinical and scientific evidence for the need of a highly specialized lifelong follow-up care due to multidimensional late effects. Furthermore, adolescence and young adulthood are challenging age periods when patients frequently get lost to follow-up potentially having severe impact on health and well-being. Since 2020, we have established a structured transfer of long-term survivors older than 18 years to a newly founded highly specialized adult care follow-up setting for childhood cancer survivors (IONA). The aim of this study was to evaluate the current transition process. RESEARCH DESIGN: The standard of care transition process at the neuro-oncology unit of the MUV includes a joint appointment with the patient, a pediatric neuro-oncologist, psychologist and/or social worker and the team of the adult care facility (physician, psychologist). Different elements are used to end care safely in the pediatric structure and building trust in the upcoming out-patient-department at the same time. The transition process was evaluated statistically and analyzed qualitatively with regard to the factors that define a safe transition. RESULTS: After two years (01/2020-12/2021) 114 patients had a joint transition appointment, two patients contacted IONA directly. Shortly after the joint appointment all patients had a scheduled follow-up meeting at IONA. 102 patients (87.9%) showed up, seven patients (6%) already had a planned appointment, two patients (1.7%) were in contact with IONA but had no possibility to show up in person. Only five patients (4.3%) did not attend the appointment and were lost to follow-up. CONCLUSION: A structured interdisciplinary transition concept is a successful option to establish controlled and patient-safe transition from pediatric to adult care setting.
RARE-31. Radiation induced malignancy associated with pediatric craniopharyngioma: a single institution experience
Authors: Franklin Chien, Matthew Schniederjan, R C Castellino, Anna Janss, Natia Esiashvili, Bree Eaton, Daniel Indelicato, Claire Mazewski
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Therapy for pediatric craniopharyngioma, a rare suprasellar tumor, includes surgical resection with consideration for intracranial radiation. Radiation is associated with increased risk of secondary malignancies. Between 2000 and 2021, 81 pediatric patients with craniopharyngioma were treated at our institution; 3 of 54 (5.6%) who received radiation therapy(RT) developed secondary malignancy within the treatment field. CASE DESCRIPTIONS: In all 3 cases, initial imaging demonstrated cystic/solid suprasellar mass and underwent resection; pathology revealed calcifications and wet keratin consistent with craniopharyngioma. None had known cancer predispositions. The first patient (male), presented at 4-years-old with headaches. He underwent subtotal resection (STR) with cyst fenestration(w/CF) and received 55.8Gy photon 3D-Conformal RT. Six-years later, the tumor progressed (edge of RT field). Patient underwent a second STRw/CF and fractionated RT(50.4Gy). Both pathologies were consistent with(c/w) papillary craniopharyngioma. Eight-years from first RT, progression occurred again within the RTfield; pathology revealed an (adeno)squamous carcinoma. The second patient, a 5-year-old female, presented with vision loss, underwent partial resection and received 54Gy focal proton therapy for adamantinonatous craniopharyngioma. Almost 5-years later, an unresectable right basal ganglia/globus pallidus mass was noted in the 30-54Gy field. Pathology was c/w anaplastic astrocytoma(AA). The third, a 9-year-old female was treated with 54Gy photon radiation and 7 years later had evidence of increasing mass. Pathology revealed high-grade-diffuse-glioma(HGDG). Molecular analysis of AA/HGDG both revealed PDGFRA amplification and CDKN2A/B homozygous loss. DISCUSSION/CONCLUSION: Malignant CNS tumors are reported following radiotherapy for a variety of primary CNS lesions. While radiation is a valuable therapy in achieving long-term disease control of pediatric craniopharyngiomas, it is important to understand the risk of developing secondary malignant neoplasms. Our report adds to the body of literature describing secondary malignancies post radiation therapy for the treatment of pediatric craniopharyngioma.